Abstract
A series of N10-substituted acridone-2-carboxamide derivatives were synthesized and evaluated for their potent anti-cancer agents targeting AKT kinase. In vitro cytotoxicity activity of the target compounds was tested against breast cancer cell lines (MCF-7 and MDA-MB-231). Among the tested compounds, four compounds (7f, 8d, 8e, and 8f) exhibited promising anti-cancer activity against both cancer cell lines. Notably, compound 8f demonstrated the highest activity against MCF-7 and MDA-MB-231 at IC50 values of 4.72 and 5.53 μM, respectively. In vitro AKT kinase activity revealed that compounds 7f and 8f were the most potent AKT inhibitors with IC50 values of 5.38 and 6.90 μM, respectively. In addition, the quantitative ELISA method of testing confirmed that compound 8f effectively inhibited cell proliferation by suppressing the activation of p-AKT Ser473. Furthermore, molecular docking studies revealed that compound 8f can bind well to the active site of the AKT enzyme. The in silico ADME studies suggested that all synthesized molecules showed good oral bioavailability with a low-toxicity profile and can be used for further optimization as AKT kinase inhibitors in the treatment of breast cancer.
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Acknowledgements
The authors are grateful to the Department of Health Research (DHR), Government of India, New Delhi, Grant/Award Number: no. V.25011/547‐HRD/2016‐HR for providing funding for research.
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TTY contributed to the study conduction, synthesis, data collection, analysis and interpretation of results, and draft/manuscript preparation; PDP was involved in the synthesis and data collection; GMS performed the molecular docking and data collection; MSK assisted in the methodology suggestions for biological studies, suggestions, and supervision, writing—reviewing and editing, and critical review of the manuscript; MC reviewed, edited, and critically revised the manuscript; MYC contributed to the conceptual design, reviewing and editing, and approval of the final version. All authors reviewed the results and approved the final version of the manuscript.
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Yadav, T.T., Patil, P.D., Shaikh, G.M. et al. Evaluation of N10-substituted acridone-based derivatives as AKT inhibitors against breast cancer cells: in vitro and molecular docking studies. 3 Biotech 13, 111 (2023). https://doi.org/10.1007/s13205-023-03524-z
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DOI: https://doi.org/10.1007/s13205-023-03524-z